Work supported by this grant has concentrated on the neurohypophysis: normal function, primary pathophysiology, and secondary pathophysiology produced by other disorders. We have developed laboratory methods of assessing neurohypophyseal function and have utilized animal models (rats) to study the pathophysiology and metabolic consequences of abnormal function. Complete diabetes insipidus is well understood, but partial loss of function is more common and less well understood. This grant utilizes new methods of solution hybridization to simultaneously quantitate mRNA of vasopressin and oxytocin, and newly developed in vivo measures of translation which will measure rate of biosynthesis and provide an index of time to process precursors. New measures of in vivo transport similarly allow quantitation of hormone transported as well as transport velocity. Each of these individual responses to accelerated hormone transported as well as transport velocity. Each of these individual responses to accelerated hormone release will be evaluated after damage to the neurohypophysis acutely and chronically to determine the mechanism of recovery. The potential for chronic morbidity after partial destruction of the neurohypophysis will be investigated by studying the risk of "recovered" animals to develop the syndrome of inappropriate antidiuresis with hyponatremia or develop diabetes insipidus when the neurohypophysis is stressed. In another model where the neurohypophysis undergoes acute and then chronic accelerated release of neurohypophyseal hormones and subsequent recovery, the mechanism of the response will be determined by the sequence of changes in message levels, translation, and transport. Changes in hormone synthesis, transport and release in the neurohypophysis will also be investigated in an animal model of chronic suppression of AVP by administration of a potent vasopressin analogue, DDAVP. Lack of down-regulation is a proposed mechanism to explain the high incidence of hyponatremia as a clinical syndrome. Immunohistologic techniques and in situ hybridization will be employed to directly identify the neurons which are involved in recovery from damage, whether new neurons are recruited and/or whether new innervation develops on the original neurons and whether the original neurons change their size and shape in response to need for increased secretion. The studies in lesioned rats are directly attributable to human dysfunction. Ongoing clinical research projects which are relevant to our understanding of the pathophysiology of the neurohypophysis and which undoubtedly respond to stress by the same mechanisms investigated in this grant will be continued. The grant brings new tools of molecular biology to the investigation of problems of immediate clinical relevance and will increase our understanding of the response of the neurohypophysis to injury, to accelerated hormone release, and to inhibition of hormone release.